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Inflammatory Bowel Disease Inflammatory Bowel Disease Chapter 2 Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease (IBD) Amir Houshang Mohammad Alizadeh Shahid Beheshti University of Medical Sciences, Taleghani Hospital, Parvaneh Ave,Tabnak Str, Evin, Tehran, Iran-19857 Phone: 0098-21-22432521; Fax: 0098-21-22432517; Email:[email protected] Abstract Primary sclerosing cholangitis is a chronic cholestatic syndrome affecting both extrahepatic and intrahepatic bile ducts that is frequently progressive, leading to liver cirrhosis, portal hypertension, and eventually to end-stage liver disease. Primary sclerosing cholangitis is strongly associated with inflammatory bowel dis- ease. The prevalence of inflammatory bowel disease (typically ulcerative colitis) among primary sclerosing cholangitis patients is approximately 70-80% while only 2-7.5% of patients with ulcerative colitis will develop primary sclerosing cholan- gitis. Primary sclerosing cholangitis is accompanied by an increased risk of liver failure, cholangiocarcinoma, and colorectal cancer. Cholangiography is considered the gold standard for the diagnosis of primary sclerosing cholangitis. It is note- worthy that medical, endoscopic, and surgical therapies do not convincingly alter disease progression in primary sclerosing cholangitis patients. Liver transplanta- tion is currently the only available therapeutic modality for patients with end-stage primary sclerosing cholangitis. 1. Introduction Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that characterized by inflammation and fibrosis with the development of bile duct stenosis. The term ‘primary’ is used to differentiate PSC from other secondary conditions including choledocholithiasis, bac- terial cholangitis, prior biliary surgery, and acquired immunodeficiency syndrome associated with cholangiopathy that may lead to a similar clinical and cholangiographic syndrome [1,2]. PSC may eventually progress to liver cirrhosis and subsequent liver failure, and is accompa- 1 Inflammatory Bowel Disease nied by an increased risk of cholangiocarcinoma. The pathogenesis of PSC remains poorly understood, however, current evidence suggests that genetic, immunologic and environmental factors appear to play key roles in the disease [3,4]. PSC is strongly associated with inflammatory bowel disease (IBD) and especially ul- cerative colitis (UC) and less often with Crohn’s disease (CD). Approximately 80% of IBD is represented by ulcerative colitis, 10% by Crohn’s disease, and 10% by indeterminate colitis. It is noteworthy that in up to 80% of cases PSC also suffering from IBD [2,5]. Although the re- lationship between PSC and IBD suggests a possible common pathogenesis, the two disorders may occur at different times [1,6]. Mohammad Alizadeh AH Alizadeh Mohammad PSC may occur in the presence or absence of IBD. IBD can be diagnosed at any time during the course of PSC, and PSC can occur at any time during the course of IBD. Given that IBD as well as PSC can be asymptomatic diseases, the time of diagnosis is driven by the clinician’s awareness of the diagnosis of disease [3,7]. The diagnosis of PSC is now most frequently established using magnetic resonance cholangiography (MRCP), although direct cholangiography may be more sensitive. Furthermore, the diagnosis of IBD and the differen- tiation between CD and UC are usually made by considering clinical, laboratory, radiological, endoscopic, and pathological criteria [2,8]. Currently, there is no effective medical therapy for PSC and liver transplantation re- mained the only treatment option. Thus, clinicians might not feel an urgency or need for early detection or diagnosis of PSC [9,10]. 2. PSC associated with IBD PSC is a chronic progressive disease, which is strongly associated with IBD (Typically ulcerative colitis [UC]). Chronic UC is most commonly associated with PSC, but patients with Crohn’s colitis also have a higher risk of developing PSC than the general population [5,11]. The relationship between PSC and UC was first shown in 1965 by Smith and Loe, and was subsequently confirmed by others. Although cause of PSC is unknown, its strong association with IBD suggests an immune dysbalance etiopathogenesis. Complex and multiple mecha- nisms are likely to be involved in PSC etiology. Current evidence suggests that genetic, im- www.openaccessebooks.com munologic and environmental factors appear to play key roles in the disease [4,12]. 3. Prevalence of PSC-IBD The prevalence and incidence of PSC-IBD varies in different series from different re- gions of the world. Furthermore, the frequency of the associated occurrence of PSC-IBD varies considerably between different studies partly due to differences in the diagnostic techniques used and probably also to differences in patients selection [13,14]. 2 Inflammatory Bowel Disease PSC is more common in men than woman (2:1 ratio), with a median presentation in the third and fourth decades of life. In addition to liver disease, PSC is closely associated with IBD. Approximately 75% of patients with PSC have IBD, and of these, nearly 80-90% are diagnosed with UC. Epidemiological studies have reported that the incidence of PSC ranges from 0.04 to 1.30 per 100000 person-years [1,11]. Conversely, it is clear that between 2.5 and 7.5% of individuals with IBD will eventually develop PSC. When further differentiated, about 3-8% of UC patients suffer from PSC, whereas among CD patients the reported prevalence of PSC is probably between 1 and 3.5% [15,16]. 4. Clinical manifestations of PSC-IBD The clinical manifestations of PSC have substantially changed through the decades. A large number of patients (44%-56%) may be without symptoms at presentation, but symptoms may develop over time [13,17]. Nowadays among symptomatic patients, fatigue and pruri- tus are the initial presenting symptoms, and with progression, these patients tend to develop jaundice, hepatomegaly, splenomegaly, abdominal pain, and weight loss. Notably, PSC may eventually progress to liver cirrhosis and subsequent liver failure, and is accompanied by an increased risk of cholangiocarcinoma. In addition, episodes of bacterial cholangitis are uncom- mon at presentation in the absence of dominant strictures or biliary manipulation and usually present with fevers, chills, right upperquadrant pain, and worsening liver biochemistries [3,11, 17]. Moreover, the association between PSC and IBD leads to specific clinical features, dif- ferent from patients with IBD alone. PSC-IBD has been reported to show an increased inci- dence of pancolitis, rectal sparing, backwash ileitis, mild symptoms, and colorectal malig- nancy [1,6]. 5. PSC and IgG4-related sclerosing cholangitis/ autoimmune pancreatitis PSC probably represents a spectrum of disease processes from classic PSC to IgG4- related sclerosing cholangitis (IgG4-SC), small-duct PSC and autoimmune sclerosing cholan- gitis, with differing clinical manifestations, disease courses and prognoses. Moreover, PSC might coexist with other immune-mediated disorders such as autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) [1,9]. IgG4-SC is a recently recognized entity which shows the cholangiographic findings similar to those of PSC. IgG4-SC is one of several diseases associated with autoimmune pan- creatitis (AIP). AIP is a chronic pancreatic condition characterized by stricturing of the pancre- atic duct, focal or generalized pancreatic enlargement, raised serum IgG4 level, lymphocytic infiltrate on biopsy. AIP in association with intrahepatic and/or extrahepatic bile duct strictur- ing similar to those present in PSC is termed autoimmune pancreatitis-sclerosing cholangitis 3 Inflammatory Bowel Disease (AIP-SC) [18,19]. The differential diagnosis of PSC from AIP and IgG4-SC is needed as the two entities show different therapeutic responses. Both IgG4-SC and AIP respond well to steroid therapy or other immunosuppressive agents and biliary drainage. In contrast, PSC is progressive and resistant to therapy, eventually involving both the intra-hepatic and extra-hepatic bile ducts and resulting in biliary cirrhosis. The rare association between IBD and IgG4-SC and the unique characteristics of PSC-IBD are useful findings for distinguishing PSC from IgG4-SC. Notably, an elevated serum IgG4 level and the association with type 1 AIP are the most useful findings for discriminating between IgG4-SC and PSC. However, elevation of the serum IgG4 level alone is not useful because some PSC cases also show increased IgG4 levels. In addition, some IgG4-SC cases are not associated with AIP [1,6,20]. 6. PSC-IBD and colorectal cancer PSC is usually a progressive disorder, which ultimately leads to severe complications including cholestasis and hepatic failure. The main causes of death in these patients are liver failure, cholangiocarcinoma (CCA), and colorectal cancer (CRC) [1,6]. PSC-IBD patients show an increased incidence of pancolitis, rectal sparing, backwash ileitis, mild symptoms, and different malignant conditions such as colorectal malignancy. The risk of development of CRC is significantly higher (Approximately four- to fivefold) among patients with PSC-IBD compared with those with IBD alone [1,13]. The association between IBD and CRC has been recognized by Crohn since 1925 and still accounts for 10%-15% of deaths in IBD. The prognosis for sporadic CRC and IBD-CRC is similar, with a 5-year sur- vival of approximately 50%. Identifying at risk patients and implementing appropriate surveil- lance for these patients is central to
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